The epidermal growth factor receptor family, which comprises four members EGFR, ErbB2, ErbB3 and ErbB4, has been demonstrated to play an important role in multiple cellular functions, including cell growth, differentiation and survival. They are protein tyrosine kinase receptors, consisting of an extracellular ligand-binding domain, transmembrane domain and cytoplasmic tyrosine kinase domain. Multiple receptor ligands have been identified which mediate receptor homo- or hetero-dimerization upon binding. The specific receptor association results in different patterns of phosphorylation, complex signaling cascades and multiple biological functions, including cellular proliferation, prevention of apoptosis and promotion of tumor cell mobility, adhesion and invasion.
Neuregulin-1 is a ligand of ErbB3 and ErbB4 receptors. Over 15 distinct isoforms of neuregulin-1 have been identified. Neuregulin-1 isoforms can be divided into two large groups, known as α- and β-types, on the basis of differences in the structure of their essential epidermal growth factor (EGF)-like domains. It has been shown that the EGF-like domains of neuregulin-1, ranging in size from 50 to 64-amino acids, are sufficient to bind to and activate these receptors. Previous studies have shown that neuregulin-1β (NRG-1β) can bind directly to ErbB3 and ErbB4 with high affinity. The orphan receptor, ErbB2, holds a pre-activated conformation to facilitate hetero-dimerization with ErbB3 or ErbB4 with approximately 100-fold higher affinity than ErbB3 and ErbB4 homodimers. The heterometric receptors act in distinct cell types: ErbB2/ErbB3 in the peripheral nervous system and ErbB2/ErbB4 in the heart. Research in neural development has indicated that the formation of the sympathetic nervous system requires an intact NRG-1β, ErbB2 and ErbB3 signaling system. Targeted disruption of the NRG-1β or ErbB2 or ErbB4 led to embryonic lethality due to cardiac development defects. Recent studies also highlighted the roles of NRG-1β, ErbB2 and ErbB4 in the cardiovascular development as well as in the maintenance of adult normal heart function. NRG-1β has been shown to enhance sarcomere organization in adult cardiomyocytes. The short-term administration of a recombinant NRG-1β EGF domain significantly improves or protects against deterioration in myocardial performance in three distinct animal models of heart failure. More importantly, NRG-1β significantly prolongs survival of heart failure animals. These effects make NRG-1β promising as a broad spectrum therapeutic or lead compound for heart failure due to a variety of common diseases. However, there is still a need for detailed structural information of NRG-1β in complex with its receptors for designing variants of NRG-1β for therapeutic use.
Numerous computational studies employing homology modeling, molecular dynamics simulations and free energy calculations have been carried out for ligand-protein and protein-protein interactions at the atomic level. Prediction of absolute ligand-receptor binding free energies is essential in a wide range of biophysical queries such as structure-based drug design. Recently, a new computational approach, the Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA), has been used for studying protein-protein interactions. MM-PBSA calculates the free energies of the end states directly to avoid the time-consuming simulation of the intermediate states. This method combines molecular mechanical energies for the solute with a continuum solvent approach and normal mode analysis to estimate the total free energies. Computational alanine-scanning methodology has also been used for studying protein-protein interactions.